The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.

Aim: To systematically summarise the current evidence of employing clinical decision support algorithms (CDSAs) using non-invasive parameters for sepsis prediction in neonates. Methods: A comprehensive search in PubMed, CENTRAL and EMBASE was conducted. Screening, data extraction and risk of bias were performed by two authors. The certainty of the evidence was assessed using GRADE. PROSPERO ID: CRD42020205143. Results: After abstract and full-text screening, 36 studies comprising 18,096 infants were included. Most CDSAs evaluated heart rate (HR)-based parameters. Two publications derived from one randomised-controlled trial assessing HR characteristics reported significant reduction in 30-day septicaemia-related mortality. Thirty-four non-randomised studies found promising yet inconclusive results. Conclusion: Heart rate-based parameters are reliable components of CDSAs for sepsis prediction, particularly in combination with additional vital signs and demographics. However, inconclusive evidence and limited standardisation restricts clinical implementation of CDSAs outside of a controlled research environment. Further experimentation and comparison of parameter combinations and testing of new CDSAs are warranted.

Background Medication-related hospital admissions (MRAs) are frequently used to measure outcomes in studies involving medication reviews. The process of identifying MRAs is subjective and time-consuming, and practical, validated alternatives are required. Objective The aim of this study was to develop and validate a practical tool to identify MRAs. Setting Uppsala University Hospital, Sweden. Method We reviewed existing literature on methods to identify MRAs. The tool AT-HARM10 was developed using an iterative process including content validity and feasibility testing. The tool’s inter-rater reliability (IRR) and criterion-related validity (CRV) were assessed: four pairs of either final-year undergraduate or postgraduate pharmacy students applied the tool to one of two batches of 50 older patients’ hospital admissions. Assessment of the same 100 admissions by two experienced clinicians acted as gold standard. Main outcome measure Cohen’s and Fleiss’ kappa for IRR, and sensitivity, specificity, and positive and negative predictive value for CRV. Results AT-HARM10 consists of ten closed questions to distinguish between admissions that are unlikely to be and those that are possibly medication-related. The IRR was moderate to substantial (Cohen’s kappa values were 0.45–0.75 and Fleiss’ kappa values were 0.46 and 0.58). The sensitivity and specificity values were 70/86% and 74/70%, positive and negative predictive values were 73/74% and 71/83% respectively. Both AT-HARM10 and the gold standard identified approximately 50% of the admissions as MRAs. Conclusion AT-HARM10 has been developed as a practical tool to identify MRAs and the tool is valid for use in older patients by final-year undergraduate and postgraduate pharmacy students. Electronic supplementary material The online version of this article (10.1007/s11096-018-0768-8) contains supplementary material, which is available to authorized users.

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The pharmacokinetics of cyclophosphamide (CP) and its cytotoxic metabolite 4‐hydroxycyclophosphamide (4‐OHCP) have been studied in multiple myeloma patients treated with the CIB (CP, interferon‐α (IFN‐α) and betamethasone) regimen. In the present investigation we aimed to determine whether exposure to CP and its cytotoxic metabolite 4‐OHCP is influenced by the concomitant administration of IFN‐α. Ten patients with previously untreated multiple myeloma entered the study. Each patient received two courses of CIB in randomized order. Interferon was administered either 2 h before the CP infusion in one course or 24 h after the CP infusion in the other course. A cyclophosphamide dose of 750–900 mg/m2 was given as a 2 h constant infusion. Interferon‐α (10–15 times 106 IE) was given subcutaneously. All patients received betamethasone 24 h after CP or later. The elimination of CP was described by monoexponential decay. The administration of IFN‐α before CP caused a decrease in CP clearance to 63% (P = 0.004), a 137% longer half‐life (P = 0.004) and a 137% higher peak plasma concentration (P = 0.006) compared to the results obtained when IFN‐α was administered 24 h after CP. The formation of 4‐OHCP was also affected by the administration of IFN‐α prior to CP, 45% less exposure to 4‐OHCP expressed as AUC (P = 0.002) and a 61% lower peak plasma concentration (P = 0.002) compared with that observed when IFN‐α was administered 24 h after CP. The administration of IFN‐α after CP resulted in a greater (45%, P = 0.02) decrease in leukocyte count compared with results when IFN‐α was given before CP. This study demonstrates that the administration of IFN‐α prior to CP significantly impairs pharmacokinetics of CP and 4‐OHCP. When IFN‐α was administered after CP, a higher exposure to the cytotoxic metabolite 4‐OHCP was observed and reflected by a significant decrease in leukocyte count compared to that when IFN‐α was given before CP. In conclusion, the time of administration of IFN‐α in relation to concomitant chemotherapy (CP) has to be considered to obtain a higher efficacy of IFN‐α/alkylating agent combining regimens for induction in multiple myeloma and related disorders.